This is an application for a K08 award for Dr. Trevor Burt, an Assistant Professor of Pediatrics in the Division of Neonatology at the University of California, San Francisco (UCSF), who is establishing himself as a young investigator in the development and function of the human fetal and neonatal immune system. This K08 award will provide Dr. Burt with the support necessary to accomplish the following goals: (1) to identify definitive gene-expression signatures for hematopoietic stem/progenitor cells (HSPC) that give rise to unique fetal (TF) and adult (TA) T cells, and using the gene-expression signatures of these HSPC and their progeny T cells; (2) to define the normal variability in the degree of TF and TA admixture in the full-term human neonate, and determine how their relative frequency (TF/TA) at birth affects neonatal immune responses; (3) to gain expertise in human stem cell biology that will prepare him to study the regulation, differentiation and function of fetal and adult HSPC populations, and finally; (4) to gain expertise in planning and executing pediatric patient-oriented research, and thereby develop an independent research career as a translational investigator. To achieve these goals, Dr. Burt has assembled a mentoring team comprised of a primary mentor, Dr. Joseph Mike McCune, Chief of the Division of Experimental Medicine at UCSF, who conducts basic and translational research in infectious disease and human immune system ontogeny, and two co-mentors: Dr. Susan Fisher, a Professor of Obstetrics, Gynecology and Reproductive Sciences, who has specific expertise in human HSPC biology; and Dr. Jennifer Puck, a Professor of Pediatrics and Director of the UCSF Pediatric Clinical Research Center, who has expertise in human immunology and pediatric translational research. Development of the human immune system, and especially the transition from the fetal tolerogenic immune response to the adult immunoreactive immune response is very poorly understood. To ultimately address problems that are specific to infection and immunization in the fetus and neonate, we must first study the normal process of this transition. The studies proposed here are designed to answer the question: is the relative frequency of fetal and adult T cells that are present at the time or birth related to the ability to mount an adaptive immune response to antigens? Dr. Burt will use the resources available to him at UCSF to: identify definitive gene expression profiles in the CD34? HSPC that give rise to fetal and adult T cells (Aim 1), characterize the normal range of fetal and adult T cell and HSPC admixture in normal full-term infants and how this admixture affects in vitro measures of T cell immunity (Aim 2), and to extend these findings to in vivo measurement of T cell immunity by studying the effects of T cell admixture on responses to neonatal vaccination (Aim 3). This will provide Dr. Burt the necessary skills and preliminary data to prepare an R01 grant application in which he will ultimately study the underlying regulatory processes that govern the transition from fetal to adult T cell predominance, and how aberrations in these processes may relate to pathology in the fetus and newborn. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Even in the era of widespread childhood vaccination, infection in the newborn period remains a leading cause of neonatal death and disease, and represents a significant public health burden due to long-term disabilities that can result from it. The unique nature of the human fetal and newborn immune system causes it to respond weakly to immunization and infections, a phenomenon that is poorly understood and greatly understudied. Defining the factors behind this weak immune response will help to alleviate the burden of neonatal infectious disease by leading to the creation of better vaccines and treatments, tailored to the newborn immune system, that will reduce the frequency and severity of infections in the newborn.